Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0008370 (cholestasis)
 9,378 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Microsomal preparations from 22 surgical specimens of normal, cholestatic or severely diseased human liver were analyzed with respect to the amounts of cytochromes P-450 and b5 and NADPH-cytochrome c reductase present. Normal human liver contained slightly less NADPH-cytochrome c reductase and cytochrome P-450 (mean 102.6 +/- 14.6 nmol/mg of protein per min. and 0.60 +/- 0.10 nmol/mg of protein, respectively) than is found in the adult rat, but wide variations were observed. Cytochrome b5 was present in comparable amounts to that in rat liver, and cytochrome b5/P --450 ratios were slightly increased in human liver as compared with rat liver. Cholestatic liver did not show significant alterations in the specific contents of any of these three components of the microsomal mixed-function oxidase system, but the two livers with severe parenchymal disease showed substantial reductions in all three. In vitro investigations of cofacter interrelationships in the N-demethylation of ethylmorphine by human liver microsomes suggested that NADPH was the favored electron donor, but NADH had a substantial (ca. 20%) synergistic effect (which was not enhanced by cyanide addition). These observations are in keeping with cytochrome b5 having a possible role in cytochrome P-450-mediated drug hydroxylation in man in both the normal state and after onset of cholestasis.
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PMID:The hepatic microsomal mixed-function oxidase system in man: cofactor effects and the influence of cholestasis. 19 27

Alterations of hepatic microsomal biotransformation in cholestasis were discussed. In experimental animals biotransformation of hypnotic and sedative drugs is impaired under cholestatic conditions in vivo. The endplasmic reticulum of the hepatocytes is hypertropic but is hypoactive with respect to drug metabolism, a condition which is partly due to interference to substances retained in cholestatic livers (bile salts) with drug biotransformation and to cytochrome P-450 diminution in the microsomal membranes. The activity of conjugating enzymes (phase II of biotransformation) remains unaffected. A similar situation exists in cholestatic patients in which drug elimination is altered. In vitro studies with human liver homogenate, microsomes, and liver slices confirm the animal experiments by showing that cytochrome P-450 as well as the metabolism of hypnotics are reduced in cholestasis.
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PMID:[Metabolism of hypnotic and sedative drugs in cholestasis (author's transl)]. 88 86

Seven days after bile duct ligation, rat receiving 80 mg of 14-C-imipramine/kg i.p. excrete less than 2 per cent of the dose as total drug (imipramine plus metabolites) within 2h through a bile fistula. In rats without cholestasis, the biliary excretion accounts for 15 per cent of the dose. The percentage of the dose found in liver, lung, brain, and blood does not differ from that found in bile fistula rats without prior bile duct ligation. The conjugates of the hydroxylated imipramine metabolites account for 33 per cent of the total drug excreted through bile after bile duct ligation as compared with 88 per cent in rats without bile duct ligation. The remaining 67 per cent of total drug are excreted as desmethylimipramine, imipramine-N-oxide and imipramine at about equal parts. Hepatic microsomal N-demethylating enzyme activity after bile duct ligation is decreased as well as the content of microsoma cytochrome P-450. A concomittant complentary appearance of the metabolically inactive cytochrome P-420 is observed.
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PMID:Influence of extrahepatic cholestasis on metabolism and biliary excretion of imipramine. 114 18

The dependence of expressiveness of microsomal mono-oxygenase induction by phenobarbital upon the amount of binding sites at cytochrome P-450 active center(s) has been studied. The experimental cholestasis is accompanied by accumulation of hydroxylated derivatives of cholesterol, which possess the detergent characteristics and destruct the substrate binding sites in P-450 molecule. The possibility has been demonstrated of phenobarbital induction under conditions when the inducer-monooxygenase primary binding and metabolic steps are not involved. It is assumed that the activation of de novo microsomal protein synthesis is effected by the molecule of phenobarbital itself and not by the products of its primary hydroxylation in the microsomes.
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PMID:[Induction of liver microsomal monoxygenases in experimental cholestasis]. 127 41

In rats, pretreatment with certain ketones results in enhanced taurolithocholic acid (TLCA)-induced reduction in bile flow, whereas pretreatment with inhibitors of protein synthesis diminishes the effect on bile flow of cholestatic regimens. In the present study, the possible role of cytochrome P-450 in the ketone potentiation phenomenon was investigated. Male rats were pretreated with inducers or inhibitors of hepatic cytochrome P-450 and the impact of these pretreatments on TLCA-induced cholestasis assessed. Phenobarbital, 3-methylcholanthrene, chlordecone or mirex were used as inducers, and SKF 525-A, piperonyl butoxide, or cobaltous chloride as inhibitors of monooxygenase activity. Phenobarbital and 3-methylcholanthrene pretreatment enhanced TLCA-induced reduction of bile flow, while mirex and chlordecone were without effect. The three inhibitors of monooxygenase activity did not diminish TLCA-induced cholestasis. Instead, piperonyl butoxide and cobaltous chloride appeared to enhance the action of TLCA. Consequently, an increase in cytochrome P-450 (or specific isozymes) as a common denominator in the potentiation phenomenon appears unlikely. While hepatic proteins may play an important role in the potentiation of TLCA-induced cholestasis following pretreatment with ketones, the pattern of potentiation after pretreatment of rats with different inducers or inhibitors of cytochrome P-450 does not appear to implicate this family of proteins.
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PMID:Influence of agents affecting monooxygenase activity on taurolithocholic acid-induced cholestasis. 128 32

The etiology of hepatocellular dysfunction resulting from chronic biliary obstruction is not clearly understood. Alterations in bile acid metabolism due to changes in microsomal cytochrome P-450 enzyme activities may have a fundamental role in cholestatic liver injury. This study examines the very early changes in both biliary bile acids and hepatic microsomal cytochrome P-450 content after bile duct obstruction in the rat and the effects of the restoration of bile flow after 3 days of biliary obstruction. We found that early induction of cytochrome P-450 may be a fundamental step in the generation of cholestatic liver injury mediated by hepatotoxic bile acids. The rapid reversal of bile acid changes with reconstituted bile flow indicate that the liver is able to quickly recover when obstruction is relieved. Characterization of this fundamental process may ultimately provide a means of modulation of cholestatic hepatotoxicity.
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PMID:Reversible bile acid changes in bile duct obstruction and its potential for hepatocellular injury. 150 Jun 78

In the present paper we provide a basic enzymatic characterization of biliary epithelial cells (BEC) that have been isolated from normal rat liver. When compared with liver parenchymal cells, BEC display the following major features: (a) a very high specific activity of gamma-glutamyltranspeptidase (approx. 200-times higher than the value usually found in hepatocytes); (b) a lack of enzymes that are usually associated with the endoplasmic reticulum in hepatocytes such as cytochrome P-450, aminopyrine demethylase, glucose 6-phosphatase and NADPH cytochrome-c reductase; (c) the presence of enzymes related to the glutathione redox cycle (e.g., GSH-peroxidase, GSSG-reductase and different isozymes of GSH-transferase), but accompanied by a very low content in reduced glutathione. The enzyme pattern of BEC correlates well with histochemical and immunohistochemical studies, as well as with biochemical studies on bile ductular cells isolated from rat liver during cholestasis.
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PMID:Biochemical studies on bile duct epithelial cells isolated from rat liver. 197 79

Male Sprague-Dawley rats were given single i.p. injections of 1,3-bis(2-chloroethyl)-1-Nitrosourea (BCNU) to investigate changes in hepatic microsomal cytochrome P-450 content and metabolic activity. On day 14 after treatment (20 mg/kg), cytochrome P-450 content had decreased by approximately 25% and ethylmorphine N-demethylase activity (nmol product/nmol P-450/min) had decreased by 36%. In contrast, ethylmorphine O-deethylase and 7-ethoxycoumarin O-deethylase activities were not significantly decreased by BCNU treatment. Hepatic delta-aminolevulinic acid synthetase activity was only 60% of control values, and microsomal heme oxygenase activity was slightly but not statistically elevated. Cytochrome P-450 content in control and BCNU-treated rats increased in a similar manner after phenobarbital or beta-naphthoflavone induction. Electrophoretic analysis of cytochrome P-450 proteins isolated from hepatic endoplasmic reticular membranes of treated and control rats suggested that alterations in these proteins occurred in BCNU-treated rats. These changes in cytochrome P-450 content and activity are very similar to those reported in isolated systems exposed to bile acids or in rats with experimentally produced cholestasis. BCNU has been shown to produce cholestasis, which precedes its effects on microsomal mixed-function oxygenase activity. Thus, the delayed effects of BCNU on microsomal drug metabolism are probably secondary to its interference with bile formation.
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PMID:BCNU-induced quantitative and qualitative changes in hepatic cytochrome P-450 can be correlated with cholestasis. 229 10

Recent work has shown that colchicine may benefit patients with primary biliary or alcoholic cirrhosis. However, very little is known about its pharmacokinetics in the presence of impaired liver function. To study this we examined the effects of three models of experimental liver dysfunction and one of cytochrome P-450 inhibition on colchicine elimination in the rat. The models of experimental liver dysfunction included bile duct ligation (with sham-operated controls), alpha-naphthylisothiocyanate-induced intrahepatic cholestasis and galactosamine-induced diffuse hepatocellular necrosis. The control group had a colchicine clearance of 77.33 ml/min.kg +/- 8.27 ml/min.kg, a half-life of 16.68 min +/- 0.97 min and a volume of distribution of 1.84 L/kg +/- 0.15 L/kg. Cimetidine administration, 120 mg/kg intraperitoneally 15 min before colchicine administration, caused clearance to decrease by 32% (p less than 0.05) and half-life to increase by 38% (p less than 0.05). Volume of distribution did not change. At 48 hr after bile duct ligation, colchicine clearance decreased by 84% (p less than 0.05), terminal half-life increased to 513.7 min +/- 106.6 min (p less than 0.05) and volume of distribution increased by 175% (p less than 0.05). Colchicine pharmacokinetics in sham-operated rats were not statistically different from the above mentioned controls.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The effect of liver dysfunction on colchicine pharmacokinetics in the rat. 230 99

Glucuronidation of 4-nitrophenol, nopol (a monoterpenoid alcohol) and bilirubin, which in the rat, are catalyzed by three different enzymes, has been examined in liver biopsies from patients with various liver diseases, in particular cholestasis. These different activities were not correlated, which strongly suggests that at least three independently regulated forms of UDP-glucuronosyltransferases were present in the microsomes. Non ionic detergents (Triton X100, Emulgen 911) and deoxycholate produced similar activation (more than 2-fold) of the glucuronidation of 4-nitrophenol. Amphipathic substances, such as CHAPS (3-[3-cholamidopropyl-dimethylammonio]-1-propane sulfonate), and lysophosphatidylcholines maximally increased this UDP-glucuronosyltransferase activity, the most potent being oleoyl lysophosphatidylcholine (4-fold increase). Discriminant analysis of the data revealed no correlation between the three different UDP-glucuronosyltransferase activities and the age or sex of the patients. A good correlation was found on multidimensional analysis between form 1 of the enzyme (4-nitrophenol glucuronidation) and, in decreasing order of magnitude, epoxide hydrolase (measured with benzo(a)pyrene-4,5-oxide as substrate), cytochrome P-450, 7-ethoxycoumarin deethylase, aspartate aminotransferase and gamma-glutamyltransferase (r = 0.89); and between Form 3 of the enzyme (bilirubin glucuronidation) and NADPH cytochrome c reductase, alkaline phosphatase, (r = 0.81). These relationships may reflect the differential variation in enzymatic activities in various hepato-biliary diseases.
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PMID:Properties of human hepatic UDP-glucuronosyltransferases. Relationship to other inducible enzymes in patients with cholestasis. 288 32


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